Abstract: We seek to understand the neuro-cellular, functional, and molecular mechanisms of age-related hearing loss (ARHL). This independent, yet inexplicably intertwined proposal is predicated on the initial compelling development and findings. In contrast to earlier reports, we found to our surprise latent neuronal degeneration of afferent spiral ganglion neuron (SGN)-hair cell (HC) synapses prior to any apparent manifestation of outer hair cell (HC) bundle disruption and HC loss, using a recognized and distinct ARHL mouse model. The mouse line has hearing characteristics similar to humans aging. We have also demonstrated functionally that the aging SGNs undergo step-wise reduction in membrane input resistance leading to reduced excitibility. Motivated by these exciting findings, we hypothesize that ?silent neuronal and synaptic degeneration? may be the preeminent target to alleviate ARHL. We propose to determine the physiological neural mechanisms of ARHL and in close collaboration with Projects (P) 1 and 3 and Cores B-C (outlined in the overal theme of the project), identify candidate genes involved and demonstrate strategies necessary to counter the disease. The overarching hypothesis of the proposal is that the aging sensory epithelia undergo structural changes that allow the high K+ endolymph to leak into the perilymph, triggering sensory-cell (HC and SGN) depolarization, increased intracellular Ca2+ ([Ca2+]i) and subsequent ?latent? synaptic and neuronal degeneration. We further hypothesize that structural changes are mediated by weakening tight junctions (TJs) in the aging sensory epithelia. Claudin 9 and Occludin are identified TJ proteins in the cochlear sensory epithelium and will be used as a prototype to test our hypotheses. Genetic mouse models carrying one allele of Cldn 9 and Ocln and doxycycline and light-mediated gene manipulations to test these hypotheses. The proposed studies will reveal critical neural mechanisms of ARHL and together with data derived from P1 and 3 and Cores B-C, new therapeutic targets for the treatment of ARHL will be assessed, tested and proposed. The results are likely to transform and shift the prevailing paradigm from descriptive to mechanistic and translational platforms.